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Elife. 2018 Sep 10;7. pii: e36158. doi: 10.7554/eLife.36158.

Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation.

Author information

1
Center for Childhood Cancer and Blood Diseases, Hematology, Oncology and BM, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, United States.
2
Medical Research Center, University of South China, Hengyang, Hunan Province, China.
3
Department of Immunology, St. Jude Children's Research Hospital, Memphis, United States.
4
Department of Surgery, St. Jude Children's Research Hospital, Memphis, United States.
5
Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, United States.
6
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, United States.
7
Markey Cancer Center, University of Kentucky, Lexington, United States.
8
Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, United States.
9
Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, Ohio, United States.
#
Contributed equally

Abstract

Upon antigen stimulation, T lymphocytes undergo dramatic changes in metabolism to fulfill the bioenergetic, biosynthetic and redox demands of proliferation and differentiation. Glutathione (GSH) plays an essential role in controlling redox balance and cell fate. While GSH can be recycled from Glutathione disulfide (GSSG), the inhibition of this recycling pathway does not impact GSH content and murine T cell fate. By contrast, the inhibition of the de novo synthesis of GSH, by deleting either the catalytic (Gclc) or the modifier (Gclm) subunit of glutamate-cysteine ligase (Gcl), dampens intracellular GSH, increases ROS, and impact T cell differentiation. Moreover, the inhibition of GSH de novo synthesis dampened the pathological progression of experimental autoimmune encephalomyelitis (EAE). We further reveal that glutamine provides essential precursors for GSH biosynthesis. Our findings suggest that glutamine catabolism fuels de novo synthesis of GSH and directs the lineage choice in T cells.

KEYWORDS:

ROS; T cells; activation; differentiation; glutathione; immunology; inflammation; mouse

PMID:
30198844
PMCID:
PMC6152796
DOI:
10.7554/eLife.36158
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

GL, JG, TW, RW, XC, LL, YS, MY, JY, YC, VV, TC, DG, YL, TF, RW No competing interests declared

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